In the early 1960s, several investigators demonstrated that opiate dependent rats and monkeys would repeatedly make responses that resulted in the intravenous delivery of morphine (Weeks, 1962; Thompson and Schuster, 1964). Subsequent research over the last 15 years has shown that non-dependent animals self-administer not only morphine but also a wide variety of other drugs, including psychomotor stimulants, barbiturates, ethanol and other opiates. Several reviews summarizing the rapidly expanding literature in this field indicate that drugs are similar to other positive reinforcers in their ability to maintain responding leading to their delivery (Schuster and Thompson, 1969; Schuster and Johanson, 1973, 1974; Goldberg, 1977; Johanson, 1978). Of particular interest is the observation that drugs which are self-administered by animals are usually considered drugs of abuse for humans. If this correlation is valid, it might be possible to use animals as a model for studying pharmacological and behavioural factors which contribute to excessive drug use in humans. One application of this model would be to use drug self-administration procedures in infra-human organisms as part of a battery for the preclinical assessment of the abuse liability of new agents.

The reinforcing efficacy or capacity of a drug can be considered one of its pharmacological properties. Like other pharmacological properties such as analgesia, however, the evaluation of reinforcing efficacy is dependent to some extent on the specific test situation, particularly when an attempt is made to quantify the property in order to compare different drugs. Researchers interested in developing a methodology for screening new compounds for their reinforcing properties are well aware of this problem. Nevertheless, it is generally believed that over a wide variety of procedures, similar qualitative results have been obtained with the drugs tested. However, in order to test this idea, an organization of interested researchers, the International Study Group Investigating Drugs as Reinforcers (ISGIDAR), sought to determine whether the results using a variety of self-administration procedures are comparable and whether these procedures can potentially be used to screen compounds for their abuse liability. The present report summarizes the findings of this group and represents the combined efforts of all the members of the organization.

One procedure which has been used extensively to measure the reinforcing properties of drugs is substitution. Animals are trained to respond on a manipulandum for drugs known to maintain responding, such as cocaine. When responding becomes stable, a dose of a test compound or vehicle (usually saline) is substituted. If saline is substituted, responding tends to decline to relatively low rates. On the other hand, when a test compound is substituted, responding may be maintained by the compound at some level above that of saline. If this occurs at any dose of a test drug, the drug is classified as a positive reinforcer. On the other hand, responding can fail to be maintained by the particular drug in a manner similar to saline, i.e. a gradual decline in response rate over several sessions. It should be emphasized that differences in the rate of responding for various drugs may be a function of many variables, only one of which is the reinforcing efficacy of the drug under study. Therefore, it is not possible using this procedure to rank drugs along a continuum of relative abuse liability. The procedure simply indicates in a qualitative manner whether or not a drug is a positive reinforcer. For instance, responding is maintained using the substitution procedure by both cocaine and diethylpropion (Johanson and Schuster, 1977). Both of these psychomotor stimulant drugs are abused by man but the incidence of cocaine use is generally recognized to be greater. However, fenfluramine, an anorexic not abused by man, does not maintain responding in animals with the substitution procedure (Tessel and Woods, 1975). Despite the qualitative nature of the data, dose-response functions do indicate differences in potency. However, these differences are not necessarily related to abuse liability.

The purpose of the present report is to summarize data generated using substitution procedures in order to assess the reliability of the results across a variety of experimental protocols, and to indicate where additional data are needed so that an evaluation of the procedure as a predictor of abuse potential can be made. For instance, if, despite differences in parameters and test situation, the results with a particular drug are consistent from laboratory to laboratory, and if these results indicate that drugs which are abused by man are self-administered by animals and drugs not abused by man are not, a case can be made for the validity of the animal model.

Because of the enormity of data which could be summarized, this report includes only selected data. The criteria used for this selection are described below. The primary criterion was whether the investigators had submitted a report of their data to ISGIDAR using the form shown in table 8. Occasionally, additional published data are included when appropiate. The failure to include certain data reports does not indicate that the studies are inappropriate, but simply that the data were not made available.

Animals. Data were selected from studies using rhesus monkeys (
Macaca mulatta). Many investigators also used rats (Weeks, 1962), cats (Balster
et al., 1976), dogs (Jones and Prada, 1973), squirrel monkeys (Goldberg, 1973), baboons (Griffiths
et al., 1975), but data using a substitution procedure with these species are not as extensive. Drugs were delivered intravenously through catheters implanted in one of several veins (e.g. internal jugular, femoral) using a variety of surgical procedures. Animals were restrained either by a primate chair or harness and arm arrangement during experimental sessions. Studies using only one animal were not included.

A drug self-administration study using substitution procedures 45

Procedure. During experimental sessions, which varied in length, responding on a manipulandum was maintained by delivery of drug (termed baseline drug) under a specified schedule of reinforcement. In almost all the reported studies, the schedule was a fixed ratio
n (
n responses required for drug delivery). The baseline drug used was known by the investigator from previous studies to maintain responding in most animals (e.g. cocaine or codeine). After responding was stable, the test drug at one dose was substituted for the baseline drug for a particular number of experimental sessions. At some point in the study, the vehicle of the test drug (usually saline) was also substituted for the baseline drug (extinction control). Several additional doses of the test drug were substituted in the same manner. Although there were some exceptions, either the baseline drug or saline was available in between the testing of each dose. Studies which tested only one dose of a test drug were not included. Responding maintained by each dose of a test drug was compared with responding maintained by the vehicle. If more than 50 per cent of the monkeys self-administered more of the test drug than saline at least at one dose, the test drug was considered a positive reinforcer.

Tables 1 to 5 show all test drugs, listed by pharmacological classes, reported to ISGIDAR whose testing met the above criteria. Whether or not the drug was self-administered is indicated in column (2). Column (3) indicates the investi-gator(s) who submitted the data to ISGIDAR. The numbers refer to the investigators listed in table 6. Table 6 also lists the adresses of the investigators. Any information concerning procedural details or results can be obtained by contacting the investigators directly. If the data are available in published form, the reference is indicated in column (4). Table 7 is a list of these references.

Using some variation of the substitution procedure, the participating laboratories of ISGIDAR have tested over 90 different compounds. As might have been expected, most of the drugs tested were well recognized drugs of abuse. However, for purposes of validation, many other types of drugs have also been tested. These include drugs presumed to have no abuse liability (e.g. imipramine, scopolamine), as well as compounds not available to the public but structurally related to an abused drug (e.g. propylamphetamine). With few exceptions (e.g., chlordiazepoxide, pentazocine, tilidine), the results obtained from different laboratories testing the same drug were in agreement. It seems therefore, that the substitution test fulfils two very important requirements for the preclinical screening of compounds: (1) many compounds can be rapidly assessed, and (2) the data are reliable across laboratories despite great variations in procedural detail.

The most important question to ask, however, is whether the substitution test is valid-i.e, are drugs which are self-administered by rhesus monkeys the same drugs that humans abuse. One of the problems in determining the answer to this question is that we are not absolutely sure about what drugs humans take in an excessive manner for non-medical purposes. There is a continuum of drugs ranging from those with considerable abuse liability to those with none. Almost everyone would agree about the status of drugs at either end of this continuum but the drugs which lie in the middle are often the subject of great debate. However, for our present purposes, our decision for saying whether or not a drug is abused by humans will be based upon our experience as experts in this area. While the reader may disagree with our decision on individual drugs, this criterion is sufficient for testing the validity of the procedure as a whole.

TABLE 1

Narcotics

Drug (1)

Result (2)

Laboratory (table 6) (3)

Reference (table 7) (4)

Agonists

1-Alpha-acetylmethadol

Yes

9

Azidomorphine

Yes

15

Codeine

Yes

4, 10, 15, 17

9, 11, 17, 25, 26

Etonitazine

Yes

9

Etorphine

Yes

15

Fentanyl

Yes

15

Heroin

Yes

4, 10, 15

11

Ketobemidone

Yes

15

Levomethorphan

Yes

15

Levorphanol

Yes

15

Meperidine

Yes

15, 17

26

Methadone

Yes

9, 15, 17

Morphine

Yes

2, 4, 9, 10, 15, 17

7, 8, 9, 17

Oxymorphone

Yes

2

d-Propoxyphene (hydrochloride)

Yes

4, 10, 15

9, 17, 29

d-Propoxyphene (napsylate)

Yes

5

29

Tilidine

Yes

10

Tilidine

No

9

Mixed agonist-antagonists

N-Amyl-nor-ketobemidone

Yes

2

Buprenorphine

Yes

15

Butorphanol

Yes

15

α-Etazocine

Yes

2

GPA-1657

Yes

2, 15

21

Nalbuphine

Yes

15

Pentazocine

Yes

10, 17

9, 11, 26

Pentazocine

No

2, 15

d,l-Profadol

Yes

10, 15

Propiram

Yes

10, 15

9, 11

Antagonists

Cyclazocine

No

10, 15

11

Ketocyclazocine

No

15

Levallorphan

No

9, 15

Nalorphine

No

1, 9, 10, 15

9, 11

Naloxone

No

15

Naltrexone

No

15

Others

Dextromethorphan

Yes

17

28

Dextrorphan

No

15

Ethoheptazine

No

15

Thebaine

No

15, 17

25

Table 1 is subdivided into narcotic agonists, mixed agonist-antagonists, antagonists and a group of miscellaneous drugs. In general, both the agonists and the mixed agonist-antagonists were positive reinforcers in the substitution procedure. This corresponds well to the general belief that any narcotic with analgesic (i.e. agonistic) properties has some potential for abuse. Except for dextro-methorphan, none of the narcotic antagonists or miscellaneous drugs function as positive reinforcers. This is also true for the non-narcotic analgesics (table 2).

In general, therefore, there is little doubt that the substitution procedure differentiates analgesics and related compounds qualitatively in terms of abuse potential. However, as previously pointed out, it does not rank these drugs in any quantitative manner. For instance, although it is generally recognized that heroin presents a more serious abuse problem than codeine, the results in the substitution procedures are similar for these two drugs.

Most of the psychomotor stimulant drugs which are positive reinforcers (table 3) are relatively similar in structure to the prototype amphetamine. In addition, these compounds are abused by humans. There are, nevertheless, stimulant drugs, such as cocaine and mazindol, which are not related structurally to amphetamine but which function as positive reinforcers. But these drugs, particularly cocaine, are also commonly abused by humans. However, there do exist compounds which are structurally related to amphetamine which are neither abused by humans nor are positive reinforcers in animals. These include chlorphentermine, fenfluramine and certain N-alkylated amphetamine derivatives. Although it is not clear what aspect of their structure is responsible for the alteration in activity, there is correspondance between their abuse and reinforcing properties. Two psychomotor stimulant drugs which are not positive reinforcers are caffeine and pemoline. These two drugs fall into the grey area where their abuse liability is a matter of debate.

Were drugs and control values obtained from the Same monkeys? .......................................... Was crossover design used? .....................................

Ethanol, as well as all barbiturates (table 4), are capable of functioning as positive reinforcers. This correlates well with their indisputable abuse potential. The results with the benzodiazepines (e.g. chlordiazepoxide) are not as clear. In fact, the most widely prescribed member of this class, diazepam, has not been tested in the substitution procedure, perhaps due to its water insolubility. Altough it has been tested under unlimited access conditions the results are equivocal (Yanagita and Takahashi, 1973). The abuse potential of this class of compounds is also questionable. Although they are widely prescribed, there is little agreement as to whether this indicates abuse. Clearly, however, more research with this class of drugs is needed.

There is little doubt that the antidepressants and major tranquillizers are neither abused nor function as positive reinforcers (table 5). However, it may be surprising that none of the hallucinogens serve as positive reinforcers (table 5) since it is generally believed that these drugs are highly abused by humans. There are two possible reasons for this discrepancy between the human and animal data. First, LSD and related hallucinogens are usually taken orally by humans and the time between dosings is generally greater than for other abused drugs. In the substitution test, these drugs were delivered intravenously and their rate of intake was compared with that of saline, which is often quite high. Therefore, the parameters of this animal model may simply be inappropriate. The second reason for the discrepancy may be that these drugs are not abused in the same manner as drugs such as cocaine or heroin. Hallucinogens may not be taken because they are positive reinforcers but because of their ability to alter some unique human behaviour such as visual imagery. Such notions, however are speculative. The best that can be said at this point is that more research with both animals and humans is necessary.

Among the miscellaneous drugs listed in table 5, it is no surprise that are-coline, ditran, pilocarpine, propanolol and scopolamine are not positive reinforcers although it is important to verify that the substitution test is capable of differentiating these types of drugs. Likewise, ketamine and particularly phencyclidine, which are known to be highly abused, were found to be positive reinforcers. There were some drugs whose results are puzzling. Nicotine, which possesses abuse potential, did not maintain responding. However, as with the hallucinogens, the intravenous route of administration may be inappropriate for testing. It is most surprising that two structurally related local anesthetics, procaine and chloroprocaine, were found to be positive reinforcers. A third, related compound, proparacaine, was not. Although procaine and chloroprocaine are structurally similar to cocaine, they are not considered drugs of abuse. Similarly, pyrilamine and diphenhydramine, both antihistamines but of different types, are not considered drugs of abuse.

In summary, most drugs which maintain responding in animals (i.e. are positive reinforcers) are considered drugs of abuse in humans. On the other hand, drugs which do not maintain responding are not abused. The only clear exceptions to this relationship are some local anaesthetics and antihistamines. Nevertheless, the high correlation between the animal and human data makes the substitution test an excellent preclinical screening procedure, particularly since it is relatively rapid and the results generated by different laboratories are comparable. While such screening procedures may help us avoid the marketing of extremely dangerous new compounds, the abuse of a drug is only to a limited extent determined by its pharmacological properties. Availability, environmental contingencies, and other complex social variables are equally important and in some circumstances may be entirely responsible for the extent of a drug's non-medical use.

- and C.R. Schuster (1977). A comparison of cocaine and diethylpropion under two different schedules of drug presentation. In:
Cocaine and Other Stimulants. E.H. Ellinwood and M.M. Kilbey (eds.). New York: Plenum Press, pp. 545-570.